The acquired immunodeficiency syndrome (AIDS) has become the fourth leading cause of death worldwide and the majority of HIV infections are acquired through heterosexual intercourse. The United Nations estimates that there are now 40 million people living with HIV/AIDS. Thus, it is urgent to develop novel therapeutic and preventative agents. Because fully effective HIV vaccines are not yet available, development of topical microbicides that block the sexual transmission of HIV is also desirable (Buckheit, R. W. (2001) Expert Opin. Investig. Drugs, 10:1423-1442; Turpin, J. A. (2002) Expert Opin. Investig. Drugs, 11:1077-1097). Naturally occurring antimicrobial peptides (AMPs) are potent host defense molecules in all life forms (Zasloff et al. (2002) Nature 415:359-365; Jenssen et al. (2006) Clin. Microbial. Rev., 19:491-511; Lehrer, R.I. (2007) Curr. Opin. Hematol., 11:16-21). More than 1,500 such peptides have been registered in the antimicrobial peptide database (APD, aps.unmc.edu/AP/main.html; Wang and Wang (2004) Nucleic Acids Res., 32:D590-D592; Wang et al. (2009) Nucleic Acids Res., 37:D933-D937). Prior to this study, 68 peptide entries in the APD are known to have HIV inhibitory activity. Some typical examples are melittin, cecropin (Wachinger et al. (1998) J. Gen. Virol., 79:731-740), LL-37 (Bergman et al. (2007) Curr. HIV Res., 5:410-5; Wang et al. (2008) Antimicrob. Agents Chemother., 52:3438-3440), α, β, and θ-defensins (Cole, A. M. (2005) Protein Pept. Lett., 12:41-47; Lehrer, R. I. (2007) Curr. Opin. Hematol., 11:16-21), cyclotides (Ireland et al. (2008) Biopolymers 90:51-60), and indolicidin (Robinson et al. (1998) J. Leukoc. Biol., 63:94-100). Because only less than 5% of the AMPs in the database have been evaluated, the APD constitutes a useful source for identifying novel HIV-inhibitory peptides. This invention discloses a database-aided discovery of new anti-HIV peptides in three different approaches: database screening, peptide sequence shuffling, and database-knowledge-based peptide design, is shown hereinbelow.